in patients with brain metastasis from melanoma, and its activity does not appear to be restricted by the blood brain barrier (46).
Colitis can be a life-threatening toxicity for patients treated with immune checkpoint blockade antibodies. With the anticipated widespread use of these reagents, the timely and accurate diagnosis of immune-related colitis becomes increasingly important. To better understand the clinical presentation of colitis from ipilimumab and to assess the use of CT scans of the abdomen/pelvis as a diagnostic tool, we retrospectively analyzed patients with advanced melanoma who received ipilimumab at our institution. Ninety nine (33%) of 303 patients developed diarrhea during therapy, and 46 patients (15%) received corticosteroids for colitis. Of the patients with diarrhea, 48 (48%) underwent colonoscopy and 46 (46%) underwent both CT and colonoscopy. In the 34 patients (34%) with a CT and biopsy, CT was highly predictive of colitis on biopsy (positive predictive value 96%), and the absence of CT findings was predictive of a negative biopsy (negative likelihood ratio 0.2). In patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (positive predictive value 92%, positive likelihood ratio 7.3). We conclude that CT is a fast, reliable, and noninvasive mode of diagnosing colitis, whereas colonoscopy and biopsy may not be needed to establish that diagnosis. .
OBJECTIVE: Correlation between EGFR/HER2 protein levels and colon cancer prognosis has been suggested. However, reports on the prevalence of EGFR/HER2 overexpression have been divergent and inconclusive due to technical variations. The uncertainty of the prevalence greatly affects decisions on therapeutic interventions targeting both molecules. We aim at evaluating the prevalence and significance of EGFR/HER2 overexpression in colon cancer cell lines. METHODS: We employed normal colon epithelial cell strain FHC and examined EGFR and HER2 levels in a series of colon carcinoma cell lines using Western blotting, and evaluated the effectiveness of siRNA targeting expression of the genes to inhibit the oncogenic properties of colon cancer cells. RESULTS: We found that (1) as compared with normal colon epithelial cells, EGFR levels and HER2 levels were significantly increased in 7 of the 8 colon cancer cell lines examined (2) siRNA targeting EGFR or HER2 reduced colony formation in soft agar of SW480 colon cancer cells, and combined treatment further reduced the colony formation ability. CONCLUSION: These results suggested that EGFR and/or HER2 elevation play an important role in the development of the majority of colon cancers, and targeting EGFR and/or HER2 could serve as an effective common strategy for therapeutic intervention or prevention of colon cancer.
Uveal melanoma (UM) is a rare form of melanoma without effective therapy. The biology of UM relies on several heat-shock protein 90 (Hsp90)-dependent molecules such as MET, MEK and AKT, making Hsp90 inhibition a rational approach. Patients with stage IV UM, measurable disease, and no previous chemotherapy were eligible. Patients received either ganetespib 200 mg weekly (cohort A) or 150 mg twice a week (cohort B). Primary endpoint response rate (RR) was assessed by RECIST. A total of 17 patients were accrued for this study, with seven in cohort A and 10 in cohort B. Liver metastases were present in 59%. Response outcomes included one partial response, four stable disease, 11 progressive disease, and one withdrawal for ORR: 5.9% and disease control rate of 29.4%. Progression-free survival was 1.6 months (cohort A) and 1.8 months (cohort B). Overall survival was 8.5 months (cohort A) and 4.9 months (cohort B). An overall 31% of adverse events were grade 3–4 and were mostly related to gastrointestinal toxicities. Early on-treatment (1 months) positron emission tomography showed reduction in metabolic activity in 24% of patients, suggesting a pharmacodynamic effect of Hsp90 inhibition. These early metabolic changes did not seem to be durable and/or clinically significant in relation to the 2-month response assessment. Hsp90 inhibition with ganetespib resulted in modest clinical benefit on two dosing schedules and was associated with significant, although manageable, gastrointestinal toxicity. Evidence of pharmacodynamic activity for Hsp90 inhibition was observed via positron emission tomography, which did not translate into clinical benefit, suggesting rapid development of resistance.
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